APPLICANT'S ABSTRACT: Breast cancer is the most common and fatal cancer among women. Recent epidemiological studies suggest that alcohol consumption increases the risk of female breast cancer, but the mechanism(s) of alcohol-caused carcinogenesis is unknown. My long-,range goal is to understand how alcohol consumption as an environmental risk factor leads to development and progression of breast cancer. The objectives of this application are to investigate the molecular mechanisms by which alcohol may contribute to breast cancer by two important actions, up-regulation of estrogen receptor-alpha (ER-alpha) activity and down-regulation of the tumor suppressor gene BRCA1. The central hypothesis of the application is that alcohol targets ER-alpha and BRCA1 as mechanisms contributory to breast cancer. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that concentrations of alcohol (ethanol, ETOH) cause: 1) down-regulation of the BRCA1 in breast cancer cells; 2) up-regulation of ER-alpha expression levels; and 3) a dose-dependent increase of up to 10-fold in ER-alpha transcriptional activity. These effects were observed at alcohol concentrations below the threshold for cytotoxicity and less than or comparable to blood levels associated with intoxication. The central hypothesis will be tested and the objective of the two-year proposal accomplished by pursuing two specific aims: 1) identify alcohol-induced alterations in ER-alpha activity and expression of estrogen-responsive genes and ER cofactors, and 2) determine effect of alcohol on expression and function of BRCA1 indifferent human breast cancer cell lines. The proposed work will be significant, because successful completion of the proposed studies, which is the next step toward attaining my long-range goal, will be to establish a mechanism to explain the association between alcohol use and breast cancer by focusing on breast cancer-specific cellular and molecular alterations.